Organic Chemistry

1. Chapter 18: Enols,Chapter 18: Enols,
Enolates, Enals, andEnolates, Enals, and
EnonesEnones
αα-Hydrogens-Hydrogens in carbonylin carbonyl
compounds arecompounds are acidicacidic

2. DeprotonationDeprotonation of a carbonyl compoundof a carbonyl compound
Bases for stoichiometricBases for stoichiometric
deprotonation: KH, LDAdeprotonation: KH, LDA
(CH(CH33))22CHCHOCHCHO ppKKaa ~ 16~ 16
CHCH33COCHCOCH33 ppKKaa ~ 20~ 20
Compare: ethene (44) or ethyne (25)Compare: ethene (44) or ethyne (25)
Dominant formDominant form
Enolates: “Oxaallyls”
Acetone enolateAcetone enolate

3. Reactivity:Reactivity: AmbidentAmbident, attack on either O or C:, attack on either O or C:
(Kinetic)(Kinetic)(Thermodynamic)(Thermodynamic)
AlkylationAlkylation ProtonationProtonation
Tautomerization

4. Keto-Enol EquilibriaKeto-Enol Equilibria
H+
or –
OH cat.
KK <<1 usually<<1 usually
We often don’t needWe often don’t need stoichiometricstoichiometric enolate formation: Acid orenolate formation: Acid or
base forms enols or enolatesbase forms enols or enolates in equilibriumin equilibrium concentrations,concentrations,
sufficient for many further transformations.sufficient for many further transformations.
H+
or –
OH cat.
Worse, because CHWorse, because CH33
stabilizes keto formstabilizes keto form
““Keto form”Keto form” ““Enol form”Enol form”

5. Mechanisms of enol to keto tautomerizationMechanisms of enol to keto tautomerization
(and the reverse):(and the reverse):
Acid-catalyzedAcid-catalyzed
Base-catalyzedBase-catalyzed

6. How is enolization detected ? MostHow is enolization detected ? Most
easily by NMR:easily by NMR: H-D exchangeH-D exchange withwith
DD22O, DO, D++
, or D, or D22O,O, --
OD (OD (αα-H signals-H signals
disappear).disappear).

7. Other consequence of enolization:Other consequence of enolization:
Loss of stereochemistryLoss of stereochemistry
CisCis
More stableMore stable
TransTrans

8. HalogenationHalogenation: uses catalytic H: uses catalytic H++
or HOor HO--
Acid-catalyzed:Acid-catalyzed:
Base-catalyzed:Base-catalyzed:
O O
Cl
+ Cl+ Cl22
HClHCl
+ HCl+ HCl
O
+ Cl+ Cl22
O
Cl
Cl
Cl
ClNaOHNaOH
+NaCl+NaCl
Stops here!Stops here!
PerchlorinationPerchlorination

9. MechanismsMechanisms: Acid-catalyzed: Acid-catalyzed
Ethenol isEthenol is
e-riche-rich
Like a Markovnikov alkene bromination
Br substituentBr substituent diminishesdiminishes thethe basicitybasicity ofof
the oxygen:the oxygen: SlowsSlows further halogenationfurther halogenation

10. Base-catalyzedBase-catalyzed
Like an SLike an SNN2 reaction2 reaction
Br substituentBr substituent increasesincreases thethe
acidityacidity of theof the αα-Hs:-Hs: SpeedsSpeeds
further halogenation.further halogenation.

11. AlkylationAlkylation
Alkylation of enolates can be difficult to controlAlkylation of enolates can be difficult to control
1. Enolate ion is a strong base: E2 problems
• Alkylation best when using halomethanes, primary
haloalkanes, or allylic halides
2. Aldehydes are attacked by enolates at carbonyl carbon
“Aldol condensation” (later)
• Better to use less reactive (at carbonyl) ketones
3. Ketones have their own problems
• Product may lose another α–hydrogen and be alkylated a
second time
• Unsymmetrical ketones lead to two regioisomeric products
LipAlknLipAlkn
BBoysBBoys

12. Only oneOnly one HH
Good alkylatingGood alkylating
agentagent

13. Solution to theseSolution to these
Problems: EnaminesProblems: Enamines
An alternative route for the alkylation ofAn alternative route for the alkylation of
aldehydes and ketones.aldehydes and ketones.
Enamines are neutral and their carbon–carbon
double bond is electron-rich.
The β-carbon is nucleophilic by resonance.
EthenamineEthenamine

14. Example:Example:
Procedure:Procedure:
1. Enamine formation using an auxiliary amine, e.g.1. Enamine formation using an auxiliary amine, e.g.
azacyclopentane;azacyclopentane;
2. Alkylation2. Alkylation
3. Acidic aqueous work-up (hydrolysis)3. Acidic aqueous work-up (hydrolysis)

15. Works also for aldehydes:Works also for aldehydes:
Important, because aldehyde enolates reactImportant, because aldehyde enolates react
with their precursor aldehydes in thewith their precursor aldehydes in the aldolaldol
condensation.condensation.

16. Aldol CondensationAldol Condensation
Can be doneCan be done
stoichiometrically withstoichiometrically with
preformed enolate.preformed enolate.
StereochemistryStereochemistry
depends on stericsdepends on sterics
New bondNew bond
CatalyticCatalytic
(Ald(Aldehyde alcohehyde alcohol)ol)

17. Examples of a catalytic aldol condensations:Examples of a catalytic aldol condensations:
50-60%
Isolable,
if wanted
(Sterically(Sterically
controled)controled)
Stepwise:Stepwise:
One pot:One pot:

18. Mechanism of Aldol Formation:Mechanism of Aldol Formation:
LipshLipsh
MonrMonr

19. Aldol Dehydration:Aldol Dehydration:
AnimnAnimn

20. The “The “crossedcrossed” aldol reaction is” aldol reaction is nonselectivenonselective......

21. ...unless a...unless a nonenolizablenonenolizable aldehyde is present:aldehyde is present:
O
O
O
H
H
H
+
NaOH, ∆
KetonesKetones may undergo aldol condensation:may undergo aldol condensation:
Endothermic
EquilibriumEquilibrium
Exothermic

22. Intramolecular AldolIntramolecular Aldol
XX XX
Strain
Thermodynamically
and kinetically
favored
StrainedStrained
bridgebridge
O
O
XX
XX
XXFour-memberedFour-membered
ring and cannotring and cannot
dehydratedehydrate
--
OH,OH, ΔΔ
-H-H22OO
Six-memberedSix-membered
ringring 90%90%GoodGood
O
XX

23. αα,,ββ-Unsaturated-Unsaturated
Aldehydes and KetonesAldehydes and Ketones
AcidicAcidic
BasicBasic
AcidicAcidic
ppKKaa ~ 16-20~ 16-20
O
HH
H
H
H
HH
H

24. 1.1. αα-Halogenation–Elimination-Halogenation–Elimination
2.2. Oxidation of Allylic AlcoholsOxidation of Allylic Alcohols
with MnOwith MnO22
RCH=CHCHRCH=CHCH22OHOH
MnOMnO22
PreparationPreparation
3. Aldol Condensation3. Aldol Condensation
O
R
H

25. 4.4. Wittig ReactionWittig Reaction – Stabilized– Stabilized
YlidesYlides
Stabilized byStabilized by
resonanceresonance::
Can be isolated,Can be isolated,
reacts only withreacts only with
aldehydesaldehydes, not, not
ketonesketones
ClCH2CH
O
P(C6H5)3
NaOH
Cl- (C6H5)3PCH2CH
O
+
(C6H5)3P CH CH
O
(C6H5)3P C
H
CH
O
(C6H5)3P
H
C CH
O
+
:
_
O
H
O
H
81%81%
TransTrans

26. Stabilized byStabilized by resonanceresonance
Properties ofProperties of αα,,ββ--
Unsaturated CarbonylsUnsaturated Carbonyls

27. Consequence:Consequence:
ββ,,γγ-Unsaturated systems-Unsaturated systems rearrangerearrange
to theto the αα,,ββ-enone isomers-enone isomers
Acid- or base-catalyzedAcid- or base-catalyzed

28. MechanismMechanism::
Acid-catalyzedAcid-catalyzed
Reprotonation
to the more
stable cation

29. Base-catalyzedBase-catalyzed

30. Reactivity ofReactivity of αα,,ββ--
Unsaturated CarbonylsUnsaturated Carbonyls
-Undergo many reactions characteristic of-Undergo many reactions characteristic of
alkenes and ketones/aldehydesalkenes and ketones/aldehydes

31. ExamplesExamples::
O O
HH22, Pd/C, Pd/C
CHCH33LiLi
O
OH
H

32. 1,4-Addition1,4-Addition (conjugate addition)(conjugate addition)
In addition, new reactivity for wholeIn addition, new reactivity for whole
system (as in conjugated dienes)system (as in conjugated dienes)

33. 1.1. Hydrogen Cyanide Conjugate AdditionHydrogen Cyanide Conjugate Addition
Not cyanohydrinNot cyanohydrin
formation (1,2-formation (1,2-
addition reversible)addition reversible)

34. MechanismMechanism::

35. 2.2. O and N NucleophilesO and N Nucleophiles
a. Ha. H22O or ROH: ConjugateO or ROH: Conjugate HydrationHydration
oror Ether FormationEther Formation
MechanismMechanism::

36. Ether FormationEther Formation: Strychnine: Strychnine
Synthesis bySynthesis by WoodwardWoodward
N
N
H
H
O
H
H
O
H
BaseBase
N
N
H
H
O
H
HO
H
StrychnineStrychnine

37. b. Amine Additions, RNHR’:b. Amine Additions, RNHR’: AminationAmination
IntramolecularIntramolecular
O
HN
O
N
--
OHOH Product mainlyProduct mainly
cis due to ringcis due to ring
fusionfusion

38. 3.3. OrganometallicsOrganometallics
RLiRLi reagents attack mainly atreagents attack mainly at C=OC=O
Cuprates,Cuprates, RR22CuLiCuLi, add, add 1,4-1,4-

39. ExampleExample of 1,4-addition with cuprate:of 1,4-addition with cuprate:
Mechanism is complex, proceeds through initial electronMechanism is complex, proceeds through initial electron
transfer (radical intermediates). We can, however, thinktransfer (radical intermediates). We can, however, think
of it as a nucleophilicof it as a nucleophilic ββ-addition. Note: Cuprates are-addition. Note: Cuprates are
organometallicsorganometallics andand moisture sensitivemoisture sensitive. The reaction is in. The reaction is in
aprotic media, therefore it generates anaprotic media, therefore it generates an enolate ionenolate ion asas
the product. Protonation occurs on work-up.the product. Protonation occurs on work-up.

40. The initial enolate product of cuprate 1,4-The initial enolate product of cuprate 1,4-
addition can beaddition can be trappedtrapped with RX:with RX: DoubleDouble
alkylationalkylation of the C=C double bond!of the C=C double bond!
Mostly transMostly trans
due to stericsdue to sterics
O
CH3
C6H5
O
1.1. (C(C66HH55))22CuLiCuLi
2.2. CHCH33II
84%84%

41. 4.4. Enolate Ions As NucleophilesEnolate Ions As Nucleophiles
Enolates attackEnolates attack αα,,ββ-unsaturated ketones-unsaturated ketones
and aldehydes in a 1,4-sense:and aldehydes in a 1,4-sense:
Michael AdditionMichael Addition (conjugate aldol addition).(conjugate aldol addition).
Works withWorks with
simple aldehydes and ketones.simple aldehydes and ketones.
MechanismMechanism::
1,5-Dicarbonyl compounds
Forms the thermodynamic enolate

42. Robinson AnnulationRobinson Annulation
CombinesCombines thethe Michael AdditionMichael Addition andand
intramolecularintramolecular Aldol CondensationAldol Condensation

43. ExampleExample::
AnimAnim
More acidic:
Benzylic (like
allylic)
Forms the thermodynamic enolate

44. Application to steroid synthesis:Application to steroid synthesis:
Acidic γ-H

45. ConjugatedConjugated
Aldehydes andAldehydes and
VisionVision

46. Vertebrates have two kind ofVertebrates have two kind of
photoreceptorphotoreceptor cells:cells:
ConesCones andand RodsRods
ConesCones
Function in bright lightFunction in bright light
Color visionColor vision
RodsRods
Function in dim lightFunction in dim light
No colorNo color

47. • Human retina has 3 million cones andHuman retina has 3 million cones and
100 million rods100 million rods
• A singleA single hhυυ of light can excite a rodof light can excite a rod
cell!cell!
• How?How?
• Rods covered with photoreceptorsRods covered with photoreceptors
• hhυυ  Atomic motionAtomic motion  NerveNerve
impulseimpulse

48. Formation of rhodopsin from the protein
opsin and 11-cis-retinal:
The process of vision isThe process of vision is
for a photon to impinge onfor a photon to impinge on
rhodopsin and effectrhodopsin and effect cis-cis-
trans isomerizationtrans isomerization. The. The
resulting geometricalresulting geometrical
change causes a nervechange causes a nerve
impulse perceived as light.impulse perceived as light.
Remember retinol = vitamin A, derived from carotene.Remember retinol = vitamin A, derived from carotene.
Deficiency causes night blindness, then blindnessDeficiency causes night blindness, then blindness
hν → cis,trans
in picoseconds
(10-12
sec)